1. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke. 2005;36(7):1588.
  2. Fortuna GR, Mueller EW, James LE, Shutter LA, Butler KL. The impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in elderly patients with hemorrhagic brain injury. Surgery. 2008;144:598-605.
  3. Wintzen AR, De Jonge H, Loelinger EA, Botts GTAM. The risk of intracerebral hemorrhage during oral anticoagulant treatment: a population study. Ann Neurol. 1984;16:533-58.
  4. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med. 2011; 365:2039-40.
  5. Noll A. Coagulation assays and the new oral anticoagulants. American College of Cardiology. June 22, 2015; Accessed April 1, 2016. Available at:
  6. The use of medicines in the United States: review of 2011. IMS Institute for Healthcare Informatics. April 2012; Accessed April 1, 2016. Available at:
  7. Protamine. Medscape Drugs & Diseases. Accessed April 1, 2016. Available at:
  8. Weber A-A, Braun M, Hohlfeld T, Schwippert B, et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol. 2001 Sep;52(3):333-6.
  9. Nylander S, Asztely AK. Reversal of ticagrelor-induced inhibition of ADP-induced platelet aggregation by the addition of uninhibited platelets in vitro. J Am Coll Cardiol. 2013;61(10_S).
  10. Brilinta [package insert]. AstraZeneca. September 2015. Available at:
  11. Praxbind [package insert]. Boehringer Ingelheim. October 2015. Available at:

Image Sources

  1. Slide 1: Image Gallery: figure 8
  2. Slide 3: Image Gallery: figure 1
  3. Slide 15:
  4. Slide 18:

Contributor Information

Roy R Danks, DO, FACOS
General and Trauma Surgeon
Heartland Surgical Specialists
A.T. Still University, Kirksville College of Osteopathic Medicine
Kirksville, MO

Disclosure: Roy R Danks, DO, FACOS, has disclosed no relevant financial relationships.


Close<< Medscape

Issues in Anticoagulation: Managing the Flow

Roy R Danks, DO  |  April 19, 2016

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Slide 1

Over the past 20 years, outpatient use of antiplatelet and anticoagulant medications has increased substantially. The introduction of novel therapies aimed at preventing platelet adherence and aggregation and countering normal blood clotting mechanisms has led to an increase in difficult-to-treat nonsurgical bleeding, especially in (though by no means limited to) the trauma population. These newer classes of medications, though offering considerable life-saving potential, come with their own set of risks. Often, the patients most likely to use and benefit from such drugs are also at substantially increased risk for spontaneous hemorrhage and traumatic hemorrhage related to other, associated disease states. Accordingly, providers who care for these patients, whether in the outpatient setting or in the acute care setting, must be aware of the hazards of these medications and the means by which to stop the complication of bleeding.

Image courtesy of Medscape.

Slide 2

The anticoagulant agents in current use may be divided into the following classes:

  • Heparinoids – Heparin, enoxaparin, dalteparin, tinzaparin
  • Vitamin K antagonists – Warfarin
  • Platelet inhibitors – Aspirin, clopidogrel, ticagrelor, dipyridamole, eptifibatide, tirofiban, prasugrel
  • Direct thrombin inhibitors – Dabigatran, lepirudin, desirudin, argatroban
  • Direct factor Xa inhibitors – Rivaroxaban, apixaban, edoxaban
  • Indirect factor Xa inhibitors – Fondaparinux

Image courtesy of Medscape.

Slide 3

In the presence of anticoagulant medications, hemorrhage that, under normal circumstances, might be self-limited—or, at least, managed less urgently—can quickly become a potentially life-threatening emergency. The main purported advantages of some of the novel oral anticoagulants (NOACs) are (1) that there are no dietary restrictions and (2) that there is no need for monitoring of blood tests, such as the prothrombin time (PT) and the international normalized ratio (INR). The latter advantage (ie, the absence of monitoring requirements) is precisely what can make it all the more difficult to manage a bleeding patient who is taking an NOAC. Relatively minor mechanisms of injury (eg, a ground-level fall or a low-velocity motor vehicle crash) can cause an astounding amount of blood loss in patients taking these medications (either singly or combined). Numerous case reports and cohort studies have shown that minor trauma can result in fatal injuries in these patients, especially when they are elderly. Current data indicate that the risk of spontaneous intracranial hemorrhage (which has a very high mortality) during oral anticoagulant therapy is in the range of 0.3-0.6%.[1] About 25% of trauma-related deaths occur in highly anticoagulated patients, and the mortality of intracerebral hemorrhage in anticoagulated patients is as high as 68%.[2,3]

Image courtesy of Medscape.

Slide 4

As indicated by the modified representation of the clotting cascade shown in the slide, numerous factors can be affected by these commonly used medications, some of which (eg, heparin and warfarin) work to block the action of multiple clotting factors. Not shown in the slide is the effect of antiplatelet medications whose action on platelets further impedes clot formation. Most providers have cared for patients who are simultaneously receiving both antiplatelet drugs and anticoagulant drugs.

Image courtesy of Medscape / Sam Shlomo Spaeth.

Slide 5

In patients who are at risk for the development of bleeding after relatively minor trauma, those in whom medical diseases can cause unexpected bleeding, and those who are seriously injured while taking antiplatelet or anticoagulant medications (or both), a rapid workup that includes laboratory and imaging studies is paramount. Routine laboratory studies should include the following:

  • Comprehensive chemistry panel
  • Hematology panel
  • Coagulation studies (PT, activated partial thromboplastin time [aPTT], and INR)

Additionally, either rotational thromboelastoplasty (ROTEM) or thromboelastography (TEG), if available (shown), can prove beneficial in determining clot strength and the need for specific clotting factors. Cotton et al, in a letter to the New England Journal of Medicine, reported that in a small group of injured patients who were taking dabigatran, the results of conventional coagulation studies were normal but the results of rapid TEG (rTEG) were markedly abnormal.[4]

Some caution should be exercised, however, with regard to the reliability of routine coagulation studies for the purpose of determining the degree of anticoagulation in patients taking NOACs. The NOACs have effects on standard anticoagulation assays that limit the assays' ability to quantify the agents' anticoagulant activity.[5]

Image courtesy of Medscape.

Slide 6

It is estimated that about 4 million patients in the United States take warfarin. In 2011, 34 million prescriptions for warfarin were written in the United States.[6] In addition, administration of the NOACs is increasing at an astonishing rate. Reversal agents exist for some, but not all, of the medications listed in slide 2. At present, there is no consensus protocol for emergency reversal of any or all of the anticoagulants—with the exception of warfarin and dabigatran, the latter of which now has a reversal agent that was approved by the US Food and Drug Administration (FDA). However, many articles have been published that address the concerns surrounding reversal and that describe the best options currently available for each agent. All healthcare institutions that may be tasked to care for these patients should have in place a plan for handling patients who are hemorrhaging while taking anticoagulants. Most antidotes are readily available at healthcare institutions. If the proper antidote for a given adverse event involving one of these drugs is unavailable, providers should promptly facilitate transfer to another location that can provide comprehensive care of these patients.

Image courtesy of Medscape.

Slide 7

Reversal of the heparinoids is achieved through intravenous (IV) administration of protamine.[7] The primary laboratory study is the aPTT, which is elevated in the presence of heparin-induced coagulopathy. Dosing is as follows:

  • Heparin neutralization – Give 1.0-1.5 mg of protamine per 100 units of heparin (total dose not to exceed 50 mg)
  • Dalteparin or tinzaparin overdose – Give 1 mg of protamine per 100 units of dalteparin or tinzaparin; if the aPTT is prolonged 4 hours after protamine overdose, administer 0.5 mg per 100 units of dalteparin or tinzaparin
  • Enoxaparin overdose – Give 1 mg of protamine per 1 mg of enoxaparin if the overdose was within 8 hours; if the overdose occurred more than 8 hours previously or if bleeding continues after 4 hours from the first dose, give 0.5 mg of protamine per 1 mg of enoxaparin

Image courtesy of Medscape.

Slide 8

Vitamin K, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are the three most commonly used reversal agents for warfarin-associated coagulopathy and hemorrhage. Administration of vitamin K in conjunction with PCC works more quickly than administration of FFP alone, and PCC replaces the factors that are inhibited by warfarin. The chief drawback to giving plasma is that the volume administered may not be well tolerated by patients with compromised cardiac output. PCC and vitamin K are low-volume medications and are generally well tolerated by patients. For the oral anticoagulants, if the medication involved was taken within 2 hours, activated charcoal should be given to bind the drug in the gastrointestinal (GI) tract.

Image courtesy of Medicimage | Visuals Unlimited (left) / Chanawit | Dreamstime (right).

Slide 9

Platelet inhibitors are being used with increasing frequency, particularly for patients with coronary artery disease (CAD) and peripheral vascular disease (PVD), in whom the patency of intra-arterial stents is critical and the risk of stroke is high. Unfortunately, the platelet inhibition induced by this class of agents is irreversible, and platelets that have been affected will remain so for at least 7 days.[8] Accordingly, patients who present with inability to clot as a consequence of irreversible platelet inhibition will require the administration of donor platelets in order to achieve platelet aggregation and clot propagation.[9] Donor platelets have a short lifespan. Because of this, repeat administrations every 3 or 4 days may be required to improve clot formation. In addition to platelet administration, desmopressin (the synthetic analogue of vasopressin) will increase factor VIII and tissue plasminogen activator levels and shorten the aPTT. Platelet aggregation is improved when desmopressin is given in the presence of clopidogrel and aspirin; however, there is a realistic concern about arterial vasospasm in the presence of desmopressin that must be taken into account, especially in patients receiving this class of medications. Ticagrelor, a P2Y12 inhibitor, reduces platelet aggregation by 70%[10]; administration of platelets will partially reverse the platelet inhibition.

Image courtesy of Ami Images | Science Source.

Slide 10

The direct thrombin inhibitors are primarily administered parenterally. Dabigatran is an exception to this general statement. It is used for reduction of stroke risk in nonvalvular atrial fibrillation, for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for reducing the risk of recurrent DVT and PE in previously treated patients. Dabigatran is commonly prescribed, currently being taken by an estimated 3.7 million patients. Lepirudin, argatroban, and desirudin are all administered IV and thus are limited to use within a healthcare facility. Nevertheless, one can imagine a scenario wherein a hospitalized patient receiving one of these medications sustains a fall and begins to bleed internally, externally, or both. In the case of the parenteral medications, administration of the drug should be stopped immediately, and coagulation, hematologic, and appropriate radiologic studies should be performed to assess for hidden hemorrhage. PCC, which contains clotting factors II, VII, IX, and X along with proteins C and S, has not been shown to be beneficial in reversing the effects of dabigatran. At present, dabigatran is the only NOAC with an FDA-approved reversal agent—namely, idarucizumab. Idarucizumab is an injectable monoclonal antibody fragment, given in a dose of 5 g IV. The package insert recommends using the ecarin clotting time (ECT) and the aPTT to evaluate for excessive anticoagulation.[11] However, the ECT is not routinely available, and other references indicate that routine clotting tests are unreliable for many if not all of the NOACs.[5] Dialysis, if available, may be used to remove as much as 60% of the drug in serum.

Image courtesy of Medscape / Sam Shlomo Spaeth.

Slide 11

Currently, no antidotes are available for reversing the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. As with all oral or parenteral agents, the medication should be stopped immediately and resuscitation efforts initiated. Although FFP is not specifically indicated for bleeding as a result of NOACs, it may be used as part of a massive transfusion protocol. PCC (if available, unactivated four-factor; otherwise, three-factor) should be given if there is imminent life-threatening bleeding. Additionally, 1 g of tranexamic acid may be administered IV, followed by 1 g over 8 hours. Rivaroxaban and apixaban are highly protein-bound and therefore are not dialyzable. Unfortunately, there are no established standards of care for the treatment of major or life-threatening bleeding in patients taking direct factor Xa inhibitors. The clinician must address individual patients and specific circumstances of bleeding on a case-by-case basis.

Image courtesy of Medscape / Sam Shlomo Spaeth.

Slide 12

At present, fondaparinux is the only indirect factor Xa inhibitor on the market in the United States. It is administered subcutaneously. No antidote is currently available for reversing fondaparinux. Routine laboratory studies should be obtained. If the PT is prolonged, vitamin K should be administered to address possible vitamin K deficiency. Administration of PCC is controversial, and the clinician should consider consulting a hematologist.

Image courtesy of Medscape / Sam Shlomo Spaeth.

Slide 13

A 65-year-old man with a history of nonvalvular atrial fibrillation presents after falling to the floor from a standing position. In the course of the fall, he struck his head on a table, and he sustained a large scalp laceration. Emergency medical services reported a large volume of blood at the scene. Attempts to control the bleeding with direct pressure have been unsuccessful. During the review of medications, the patient states that he takes warfarin at a dosage of 3 mg/day. His blood pressure is 80/50 mm Hg, and his heart rate is 110 beats/min and irregularly irregular.

Which of the following laboratory studies will be most expedient and useful for determining this patient's degree of anticoagulation?

  1. aPTT
  2. PT with INR
  3. Factor Xa level
  4. Bleeding time
  5. Complete blood count (CBC)

Image courtesy of Dr P Marazzi / Science Source.

Slide 14

Answer: B. PT with INR.

Assessment of the degree of anticoagulation in a patient taking oral anticoagulants requires that both the PT and the INR be obtained. Warfarin, a vitamin K antagonist, will result in a prolonged PT and an elevated INR.

Image courtesy of Jarun011 |

Slide 15

The patient's PT and INR are found to be significantly elevated (PT, 6.1 sec; INR, 11). The scalp laceration continues to bleed, and a computed tomography (CT) scan of the head shows an acute subdural hematoma.

Which of the following is the most appropriate next step in caring for this patient?

  1. Transfer to a verified trauma center
  2. Administration of vitamin K, 10 mg IV
  3. Administration of tranexamic acid, 1 g IV
  4. Administration of a platelet pack
  5. Administration of idarucizumab

Image courtesy of Prof Frank Gaillard | Radiopaedia.

Slide 16

Answer: B. Administration of vitamin K, 10 mg IV.

In addition to PCC, vitamin K should be administered to this patient. Warfarin is a vitamin K antagonist; therefore, reversal is accomplished by administering the direct agonist. If PCC is not available, FFP is the next most appropriate therapy.

Image courtesy of Medscape / Sam Shlomo Spaeth.

Slide 17

A 26-year-old woman with a recent history of venous thromboembolism (VTE) and PE presents with multiple episodes of orthostatic syncope. Three months previously, she started taking rivaroxaban for treatment of VTE. On the day of her admission to the emergency department, the patient was involved in a slow-speed motor vehicle crash, in which she was wearing a seat belt. On examination, a large area of ecchymosis is noted across the lower abdomen, correlating with the location of the seat belt. A trauma sonogram of the abdomen and pelvis is obtained and is normal.

Which of the following is the most appropriate study to perform next?

  1. Tagged red blood cell (RBC) bleeding study
  2. Magnetic resonance imaging (MRI)
  3. CT with IV contrast
  4. Plain radiography of the abdomen and pelvis

Image courtesy of Dreamstime | Shannon Fagan.

Slide 18

Answer: C. CT with IV contrast.

A major concern in this case is the potential presence of retroperitoneal bleeding. Accordingly, the most appropriate next step in the assessment of this patient is CT of the abdomen and pelvis with IV contrast. Seat belt injuries are less common in low-velocity motor vehicle crashes; however, because the patient is taking an NOAC (rivaroxaban), she is at increased risk for significant bleeding even with relatively minor trauma.

Image courtesy of National Library of Medicine | Sun PL, Lee YC, Chiu KC.

Slide 19

Which of the following is not a potential treatment for rivaroxaban-associated hemorrhage?

  1. Administration of PCC
  2. Administration of tranexamic acid
  3. Administration of blood and blood products
  4. Dialysis

Image courtesy of Medscape.

Slide 20

Answer: D. Dialysis.

As previously noted (see slide 11), rivaroxaban and apixaban are both highly protein-bound. For this reason, dialysis is a treatment that should not be considered.

Image courtesy of Can Stock Photo Inc.

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